Nephritogenic cytokines and disease in MRL-Faslpr kidneys are dependent on multiple T-cell subsets

T. Wada, A. Schwarting, M. S. Chesnutt, D. Wofsy, V. R. Kelly

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Background. Renal parenchymal cells produce cytokines, colony-stimulating factor-1 (CSF-1), granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor-α (TNF-α), which recruit autoreactive T cells and, in turn, elicit renal injury in MRL-Faslpr mice. Methods. To determine whether select T-cell populations regulate intrarenal nephritogenic cytokines (CSF-1, GM-CSF, and TNF-α) and renal disease, we compared MRL-Faslpr mice that are genetically deficient in T-cell receptor (TCR) αβ T cells, CD4 T cells, and major histocompatibility complex class I (MHC class I), lacking CD8 and double negative (DN) T cells, with wild-type mice. To identify the T cells instrumental in downstream (effector) events, we delivered CSF-1 or GM-CSF into the kidney via gene transfer in these select T-cell-deficient and wild-type strains. Results. Intrarenal CSF-1, GM-CSF, and TNF-α were absent or dramatically reduced in TCR αβ, CD4, and class I-deficient MRL-Faslpr strains as compared with wild-type mice. In addition, the decrease in CSF-1, GM-CSF, and TNF-α was associated with a reduced kidney leukocytic infiltrates and spontaneous autoimmune nephritis. Intrarenal ex vivo retroviral gene transfer of CSF-1 and GM-CSF failed to elicit nephritis in these T-cell-deficient MRL strains (TCR αβ, CD4, CD8/DN) as compared with wild-type mice. Conclusions. Multiple T-cell populations initiate renal disease by increasing intrarenal nephritogenic cytokines, CSF-1, GM-CSF, and TNF-α. CSF-1 and GM-CSF recruit additional CD4 and CD8 and DN T cells, which augment downstream events, resulting in progressive autoimmune renal disease. We suggest that MRL-Faslpr kidney disease is driven by a T-cell amplification feedback loop dependent on multiple T-cell populations.

Original languageEnglish (US)
Pages (from-to)565-578
Number of pages14
JournalKidney International
Volume59
Issue number2
DOIs
StatePublished - Jan 1 2001

Keywords

  • CSF-1
  • GM-CSF
  • Gene transfer
  • Lupus nephritis
  • Macrophages
  • TNF-β

ASJC Scopus subject areas

  • Nephrology

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